Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely consumed pharmaceuticals, but their prolonged use causes gastric injury and damage to the small intestine. Previous work has shown that anandamide, an endogenous endocannabinoid substance produced in the gastrointestinal (GI) mucosa, plays an important role in epithelial homeostasis and repair. The biological actions of anandamide are terminated by the intracellular enzyme, fatty acid amide hydrolase (FAAH). To explore the role of anandamide in peripheral tissues, we have recently developed a novel class of small-molecule FAAH inhibitors that suppress anandamide deactivation only in the periphery of the body. Previous selectivity, safety and pharmacokinetic studies have identified the prototype member of this class, a compound called URB937, as a potential lead candidate for preclinical development. We recently discovered that URB937 suppresses NSAID-induced gastric damage in animal models by amplifying a protective feedback mechanism mediated by endogenously produced anandamide. These results suggest that URB937 might offer a transformative approach to prevent and/or treat gastric and intestinal damage associated with prolonged NSAID use. Our proposal has two primary goals: (1) Determine the comparative efficacy of URB937 in a model of acute NSAID-induced gastric damage. We will investigate the effects of different oral dosages of URB937, and compare them to those of two gastroprotectant drugs currently employed in the clinic (omeprazole and misoprostol), in a standard preclinical model of acute NSAID-induced gastropathy (using the potent NSAID, indomethacin). (2) Determine the efficacy of URB937 in the prevention of chronic NSAID-induced gastric and intestinal damage. We will examine whether URB937 can (i) prevent the gastropathy and enteropathy elicited by chronic indomethacin; and (ii) prevent the gastropathy produced by chronic aspirin. These models mimic two distinct settings where the GI-protecting effects of URB937 might find clinical application: healing of NSAID-associated GI damage in patients continuing NSAID therapy, and prevention of peptic ulcers in cardiovascular patients taking low-dose aspirin. Development of URB937 will be continued if the compound fulfills at least one of the following criteria (i) activiy in preventing GI damage produced by acute and chronic indomethacin, or (ii) activity in preventing gastric damage produced by chronic aspirin. If either or both of these criteria is met, we will apply for STTR Phase 2 funding to move URB937 to full preclinical development for NSAID gastroenteropathy.